Simple and rapid quantification of serotonin transporter binding using [¹¹C]DASB bolus plus constant infusion

In-vivo quantification of serotonin transporters (SERT) in human brain has been a mainstay of molecular imaging in the field of neuropsychiatric disorders and helped to explore the underpinnings of several medical conditions, therapeutic and environmental influences. The emergence of PET/MR hybrid systems and the heterogeneity of SERT binding call for the development of efficient methods making the investigation of larger or vulnerable populations with limited scanner time and simultaneous changes in molecular and functional measures possible. We propose [¹¹C]DASB bolus plus constant infusion for these applications and validate it against standard analyses of dynamic PET data.

[¹¹C]DASB bolus/infusion optimization was performed on data acquired after [¹¹C]DASB bolus in 8 healthy subjects. Subsequently, 16 subjects underwent one scan using [¹¹C]DASB bolus plus constant infusion with K_bol 160-179min and one scan after [¹¹C]DASB bolus for inter-method reliability analysis. Arterial blood sampling and metabolite analysis were performed for all scans. Distribution volumes (V_T) were obtained using Logan plots for bolus scans and ratios between tissue and plasma parent activity for bolus plus infusion scans for different time spans of the scan (V_T-70 for 60-70min after start of tracer infusion, V_T-90 for 75-90min, V_T-120 for 100-120min) in 9 subjects. Omitting blood data, binding potentials (BP_ND) obtained using multilinear reference tissue modeling (MRTM2) and cerebellar gray matter as reference region were compared in 11 subjects.

A K_bol of 160min was observed to be optimal for rapid equilibration in thalamus and striatum. V_T-70 showed good intraclass correlation coefficients (ICCs) of 0.61-0.70 for thalamus, striatal regions and olfactory cortex with bias ≤5.1% compared to bolus scans. ICCs increased to 0.72-0.78 for V_T-90 and 0.77-0.93 for V_T-120 in these regions. BP_ND-90 had negligible bias ≤2.5%, low variability ≤7.9% and ICCs of 0.74-0.87; BP_ND-120 had ICCs of 0.73-0.90. Low-binding cortical regions and cerebellar gray matter showed a positive bias of ~8% and ICCs 0.57-0.68 at V_T-90. Cortical BP_ND suffered from high variability and bias, best results were obtained for olfactory cortex and anterior cingulate cortex with ICC=0.74-0.75 for BP_ND-90. High-density regions amygdala and midbrain had a negative bias of -5.5% and -22.5% at V_T-90 with ICC 0.70 and 0.63, respectively.

We have optimized the equilibrium method with [¹¹C]DASB bolus plus constant infusion and demonstrated good inter-method reliability with accepted standard methods and for SERT quantification using both V_T and BP_ND in a range of different brain regions. With as little as 10-15min of scanning valid estimates of SERT V_T and BP_ND in thalamus, amygdala, striatal and high-binding cortical regions could be obtained. Blood sampling seems vital for valid quantification of SERT in low-binding cortical regions. These methods allow the investigation of up to three subjects with a single radiosynthesis.